Metabolic brain disease最新文献

Introduction: Changpu Yujin Tang(CPYJT), a Chinese herbal compound, is an effective therapeutic strategy for pediatric patients with Tourette disorder (TD). Therefore, this work aims to investigate the therapeutic mechanisms of CPYJT.

Methods: Behavioral and cellular ultrastructural evaluation of the therapeutic effects of CPYJT in TD model rats. Colorimetric methods, reverse transcription‑quantitative PCR, and Western Blot were used to measure the altered levels of GLU, GABA, and the levels of VGLUT1, GLUD1, GABRA3, and GAD65 in the cortex, striatum, and thalamus of the TD model rats after 7, 14, 21, and 28 days of CPYJT administration.

Results: CPYJT significantly reduced stereotypic behavior and motor behavior scores in TD model rats. CPYJT ameliorates myelin structural damage in TD model rat neuronal cells. CPYJT decreased GLU content, elevated GABA content, decreased GLUD1 and VGLUT1 levels, and elevated GAD65 and GABRA3 levels in TD model rats' cortex, striatum, and thalamus. CPYJT has different regulatory time points in the cortex, striatum, and thalamus for critical factors of amino acid-based neurotransmission.

Conclusion: CPYJT protects behavioral and structural damage of neuronal cells in multiple brain regions in TD model rats.

The study examined curcumin’s impart on relieving neuroinflammation of juvenile rats in kainic acid (KA) induced epileptic seizures by inhibiting the TLR4/MyD88/NF-κB pathway. There were five groups: control, KA, KA + curcumin (KC), KA + oxcarbazepine (OXC) (KO), KA + curcumin + OXC (KCO) groups. KA was stereotactically injected into right hippocampus following intraperitoneal injection of curcumin or (and) OXC for seven days. The rats in the above groups were randomly divided into three subgroups (at 6 h, 24 h, and 72 h of KA administration) following the seizure degree assessed. The number of NeuN (+) neurons and GFAP (+) astrocytes was counted. The gene and protein levels of TLR4, MyD88, and NF-κB were detected. Compared with the KA group, the seizure latency was longer, and the incidence of status epilepticus (SE) was lower in the KC, KO, and KCO groups. The most significant changes were in the KCO group. At 72 h following KA injected, the number of neurons was the least, and the number of astrocytes was the most in the KA group. The number of neurons was the most and the number of astrocytes was the least in the KCO group. At 24 h, the mRNA and protein levels of TLR4, MyD88, and NF-κB in the KA group were the most. The above valves were the least in the KCO group. Therefore, curcumin could enhance anti-epileptic effect of OXC, protect injured neurons and reduce proliferated glial cells of the hippocampus of epileptic rats by inhibiting inflammation via the TLR4/MyD88/NF-κB pathway.

Several recent studies have attempted to understand how fasting has benefits for body health, especially the nervous system. To evaluate the impact of intermittent fasting on body weight, brain neurotransmitters, brain oxidative stress, and brain-derived neurotrophic factor (BDNF) in several areas of the brain, this study was conducted in rats. Thirty male Wistar rats were randomly divided into two groups. Group 1 (15 rats) served as the control and group 2 (15 rats) underwent intermittent fasting (IF; 24 h) for 1, 7, or 15 days. The findings demonstrated that intermittent fasting significantly reduced body weight. In this sense, brain monoamines and amino acids, namely dopamine, glutamate, aspartate, and oxidative stress markers (malondialdehyde and nitric oxide), decreased significantly after 1 day of IF. However, norepinephrine, serotonin, gamma-amino butyric acid, and glycine increased significantly. Additionally, glutathione levels were markedly elevated in IF. Surprisingly, the neuromodulatory effect of intermittent fasting fluctuates depending on the IF period. To support this fluctuation, BDNF levels increased after 1 day in the hippocampus and decreased after 15 days of intermittent fasting in all areas of the brain tested. In conclusion, our results show that intermittent fasting has beneficial influences on the brain; however, prolonged intermittent fasting can also induce some unfavorable physiological outcomes that prevent optimal neurological function.

Exposure to chronic stress impairs memory. Also, escitalopram's impact on memory remains paradoxical. Therefore, this study examined how prolonged escitalopram administration affects input-output (I/O) functions, paired-pulse ratio (PPR), and long-term potentiation (LTP) in the hippocampal CA1 area in rats that underwent predictable and unpredictable chronic mild stress (PCMS and UCMS, respectively). Male rats were randomly assigned to different groups of control (Co), sham (Sh), PCMS and UCMS (PSt and USt, respectively; 2 h/day, for 21 consecutive days), escitalopram (Esc; 10 mg/kg, i.p., for 21 days), as well as PCMS and UCMS with escitalopram (PSt-Esc and USt-Esc, respectively). The fEPSP slope, amplitude, and area under the curve (AUC) were assessed in the hippocampal CA1 area using I/O functions, PP responses, and LTP. Serum corticosterone (CORT) levels were quantified in all experimental animals. The slope, amplitude, and AUC of fEPSP in the I/O functions, and all three PP phases prior and subsequent to LTP induction significantly declined in the USt and PSt groups. Escitalopram significantly enhanced these parameters in the PSt-Esc, but not in the USt-Esc group. Serum CORT levels corroborated the electrophysiological findings among experimental groups. Both PCMS and UCMS impaired neural excitability, neurotransmission, and memory within the hippocampal CA1 area. Escitalopram improved memory impairment only under PCMS, potentially attributed to reduced serum CORT levels. However, no influence on neural excitability, neurotransmission, and memory was observed under UCMS. This suggests different escitalopram doses might be required to ameliorate simultaneous mechanisms in response to various types of chronic mild stress.

Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. The cleavage factor Im 25 (CFIm25), a crucial component of the CFIm complex, plays a key role in regulating the length of the mRNA 3'-UTR and has been implicated in various cancers, including GBM. This study sought to investigate the regulatory influence of specific microRNAs (miRNAs) on CFIm25 expression in GBM, a highly aggressive brain tumor. Bioinformatics analysis identified miRNA candidates targeting CFIm25 mRNA, and gene expression profiles from the NCBI database (GSE90603) were used for further analysis. Expression levels of CFIm25 and selected miRNAs were assessed using qRT-PCR in GBM clinical samples (n = 20) and non-malignant brain tissues (n = 5). Additionally, the MTT assay was performed to examine the effect of miRNA overexpression on U251 cell viability. Lentivectors expressing the identified miRNAs were employed to experimentally validate their regulatory role on CFIm25 in U251 cell lines, and Western blot analysis was conducted to determine CFIm25 protein levels. We observed significantly increased levels of miR-23, miR-24, and miR-27 expression, associated with a marked reduction in CFIm25 expression in GBM samples compared to non-malignant brain tissues. In particular, overexpression of miR-23, miR-24, and miR-27 in U251 cells resulted in CFIm25 downregulation at both the mRNA and protein levels, while their inhibition increased CFIm25 and reduced cell proliferation. These observations strongly implicate miR-23, miR-24, and miR-27 in regulating CFIm25 expression in GBM, emphasizing their potential as promising therapeutic targets for enhancing treatment responses in glioblastoma.

Neurological disorders are the primary cause of human disability and mortality globally, however, current medications slightly alleviate some symptoms of degenerative diseases. Serine is an important amino acid for the brain function and involved in a variety of biosynthetic pathways and signal transduction processes. The imbalance of serine metabolism is associated with neurodegeneration, including neuroinflammation, oxidative stress and apoptosis. Altered activities of serine metabolizing enzymes and accumulation of serine metabolites affect the survival and function of nerve cells. Abnormal serine levels are observed in animal models with neurological diseases, but not all human studies, therefore, the maintenance of serine homeostasis is a potentially therapeutic strategy for neurological disorders. To date, physiological and pharmacological roles of serine in neurological diseases have not been systemically recapitulated, and the association between serine and neurological diseases is controversial. In this review, we summarize physicochemical properties of serine, biological processes of serine in the brain (source, biotransformation, and transport), and the application of serine in neurological diseases including Alzheimer's disease, schizophrenia, and depression. Here, we highlight physicochemistry, physiology, pharmacology, and therapeutic potentials of serine in the prevention and treatment of neurological dysfunction. Our work provides valuable hints for future investigation that will lead to a comprehensive understanding of serine and its metabolism in cellular physiology and pharmacology. Although broad by necessity, the review helps researchers to understand great potentials of serine in the prevention and treatment of neurological dysfunction.

The mostly aggressive and extremely malignant type of central nervous system is Glioblastoma (GBM), which is characterized by an extremely short average survival time of lesser than 16 months. The primary cause of this phenomenon can be attributed to the extensively altered genome of GBM, which is characterized by the dysregulation of numerous critical signaling pathways and epigenetics regulations associated with proliferation, cellular growth, survival, and apoptosis. In light of this, different genetic alterations in critical signaling pathways and various epigenetics regulation mechanisms are associated with GBM and identified as distinguishing markers. Such GBM prognostic alterations are identified in PI3K/AKT, p53, RTK, RAS, RB, STAT3 and ZIP4 signaling pathways, metabolic pathway (IDH1/2), as well as alterations in epigenetic regulation genes (MGMT, CDKN2A-p16^INK4aCDKN2B-p15^INK4b). The exploration of innovative diagnostic and therapeutic approaches that specifically target these pathways is utmost importance to enhance the future medication for GBM. This study provides a comprehensive overview of dysregulated epigenetic mechanisms and signaling pathways due to mutations, methylation, and copy number alterations of in critical genes in GBM with prevalence and emphasizing their significance.

Many patients with liver cirrhosis show minimal hepatic encephalopathy (MHE) with mild cognitive impairment (MCI) and motor alterations that reduce their quality of life. Some patients with steatotic liver disease also suffer MCI. To design treatments to improve MHE/MCI it is necessary to understand the mechanisms by which liver disease induce them. This review summarizes studies showing that appearance of MHE/MCI is associated with a shift in the immunophenotype leading to an "autoimmune-like" form with increased pro-inflammatory monocytes, enhanced CD4 T and B lymphocytes activation and increased plasma levels of pro-inflammatory cytokines, including IL-17, IL-21, TNFα, IL-15 and CCL20. The contribution of peripheral inflammation to trigger MHE is supported by studies in animal models and by the fact that rifaximin treatment reverses MHE in around 60% of patients in parallel with reversal of the changes in peripheral inflammation. MHE does not improve in patients in which peripheral inflammation is not improved by rifaximin. The process by which peripheral inflammation induces MHE involves induction of neuroinflammation in brain, with activation of microglia and astrocytes and increased pro-inflammatory TNFα and IL-1β, which is observed in patients who died with steatotic liver disease (SLD) or liver cirrhosis and in animal models of MHE. Neuroinflammation alters glutamatergic and GABAergic neurotransmission, leading to cognitive and motor impairment. Transmission of peripheral alterations into the brain is mediated by infiltration in brain of extracellular vesicles from plasma and of cells from the peripheral immune system. Acting on any step of the process peripheral inflammation - neuroinflammation - altered neurotransmission may improve MHE.